Abstract 3507: Type 17-1-CD8+ T cells (Tc17-1) as potent effector cells for immunotherapy of brain tumors

Abstract

Abstract Malignant gliomas, such as glioblastoma multiforme (GBM), are the most common and dismal primary brain tumors, and there is a strong need for developing novel and effective therapeutic modalities. Although the central nervous system (CNS) and CNS tumors are often considered immunologically privileged, as demonstrated by studies on CNS autoimmunity, activated autoreactive T-cells, especially T helper (Th) 17 cells, infiltrate through the blood brain barrier (BBB) and mediate antigen-specific responses in the CNS. Especially, Th17 express high levels of CCR6, which has a crucial role in Th17 infiltration into the CNS. In addition to Th17 cells, a new putative subtype of IL-17-producing CD4+ T cells with CD4+IL-17+IFN-γ+ (Th17-1 cells) double-positive phenotype has also been identified. Based on our previous studies demonstrating a critical role of Th1-chemokine CXCL10 and its receptor CXCR3 for effective T-cell trafficking in CNS tumors, we hypothesized that Th17-1 cells and CD8+ T cells producing IL-17 and IFN-γ (hereby Type-17-1 CD8+ T-cells) will demonstrate superior CNS tumor infiltration compared with Th1 cells due to the activation of two CNS-relevant chemokine pathways, CXCL10-CXCR3 and CCL20-CCR6. Mouse Tc17, Tc17-1 and Tc1 cells generated from Pmel-1 mouse-derived naïve CD8+ T cells expressed high CCR6 and low CXCR3, high CCR6 and high CXCR3, and little CCR6 and high CXCR3, respectively. Although Tc17 displayed lower levels of antigen-specific cytotoxic activity compared with Tc17-1 and Tc1 in a 4 hr cytotoxic assay, Tc17 killed tumor cells more effectively than the other populations in long-term cultures (4 to 6 days). While Tc1 cells underwent apoptosis due to their exhausted state, Tc17-1 maintained strong cytotoxicity and proliferative activities even after 4 day co-culture with tumor cells. Moreover, the supernatant derived from activated Tc17 and Tc17-1 induced CCL20 and CXCL10 in the GL261 glioma cells while Tc1-derived supernatant induced CXCL10 but not CCL20. These results suggest a possibility that Tc17-1 may elicit persistent anti-CNS tumor responses and induce both CCL20 and CXCL10 in the CNS tumor microenvironment, thereby attracting additional effector cells to the site. In vivo studies in mice bearing CNS gliomas are warranted to determine whether adoptively transferred Tc17-1 infiltrate to the CNS tumor site and mediate superior anti-tumor response compared with Tc1. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3507. doi:1538-7445.AM2012-3507